The Centers for Disease Control and Prevention estimates that nearly two thirds of the American population is either overweight or obese, due in part to a chronic consumption of a high fat diet (HFD). Emerging data strongly suggests that the brain is sensitive to the detrimental effects of excessive adiposity. These observations have led to a rapidly growing area of research designed to map the influence of dietary fat and excess adiposity on the brain, particularly in regards to the onset and progression of age-related dementias. For example, recent epidemiological studies suggest that increased adiposity, and specifically visceral adiposity, elevates the risk of both vascular dementia and Alzheimer's disease (AD). Furthermore, data from our laboratory and others have clearly demonstrated that diet-induced adiposity in rodents elicits multiple neurologic disturbances including cognitive impairment and increased markers of oxidative stress. All of these data point to a significant role for HFD and visceral adiposity as potentially important clinical modulators of Abeta- associated dementias. However, at present the extent to which, and the mechanisms by which, dietary fat and adiposity regulate Abeta pathogenesis in the brain is not yet known. This proposal will test the hypothesis that dietary induced obesity promotes alterations in Abeta pathology, and corresponding increases in the downstream components of Abeta pathogenesis, that are dependent in part on increases in visceral adiposity. Secondly, this proposal will test the hypothesis that increased levels of visceral adiposity are sufficient to promote Abeta pathology, and the downstream components of Abeta pathogenesis. This proposal is therefore designed to address (for the first time) the critical questions as to whether increased visceral adiposity is necessary for HFD/obesity-induced effects on the brain, as well as address whether increased visceral adiposity is sufficient to increase brain pathogenesis. The focus of experimentation will be on the modulation of Abeta pathology, and the consequences of Abeta pathology, using a mouse model of cerebral amyloid angiopathy (CAA). CAA was selected for these studies since it is both a pathological substrate for vascular dementia, as well as a common co-pathology within the AD brain (present in ~80% of AD cases). These studies will comprehensively analyze the continuum of Abeta pathogenesis in the context of changes in adiposity, metabolism, neurobehavior, and neurochemistry. Completion of the proposed studies will provide the first quantitative measures on each of the following questions. Is increased visceral adiposity necessary for dietary induced obesity promotion of Abeta pathology? Is increased visceral adiposity sufficient to induce alterations in Abeta pathology? How do these effects of visceral adiposity towards Abeta pathology relate to specific behavioral and molecular indices of brain injury?